Selective substitutions in the C10-methyl group in erythromycin derivatives

Article abstract of DOI:10.1016/j.tet.2006.03.098

A method for chemical modifications of the relatively unreactive C10-methyl group in the erythromycin macrolactone ring has been developed. Erythralosamine was protected as an N-oxide in the N,N-dimethylamino group and reacted with NBS in acetic acid to p

Full text of DOI:10.1016/j.tet.2006.03.098

Tetrahedron 62 (2006) 6090–6099
Selective substitutions in the C10-methyl group in
erythromycin derivatives
*
Sølvi Gunnes, Christian Rømming and Kjell Undheim
Department of Chemistry, University of Oslo, N-0315 Oslo, Norway
Received 3 February 2006; revised 14 March 2006; accepted 30 March 2006
Available online 9 May 2006
Abstract—A method for chemical modifications of the relatively unreactive C10-methyl group in the erythromycin macrolactone ring has
been developed. Erythralosamine was protected as an N-oxide in the N,N-dimethylamino group and reacted with NBS in acetic acid to provide
two regioisomeric allylic bromides. The same amine was formed from both isomers on nucleophilic substitution. Both regioisomeric bromides
in cross-coupling reactions under Stille conditions provided the same product from substitution in the 10-methyl group via a common
p-allylic palladium complex. Under Negishi conditions with trimethylalane, the Pd-catalysed cross-coupling provided the 10-ethyl
homologue. X-ray analyses were used to confirm the structure of erythralosamine, and to determine the structures of the allylic bromides
from erythralosamine N-oxide.
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
A chemical approach for modification of the C10-methyl
group, however, was suggested by a structural analysis of
the acidic degradation product 2 from erythromycin A (1)
The erythromycin family of macrolactone antibiotics com-
prises an important group of antibiotics widely used clini-
7
in Scheme 1. The same product, erythralosamine, is gener-
1
–3
cally.
The parent drug has been subjected to a number
ated in the acidic environment in the stomach during meta-
bolic degradation of erythromycin as a drug. In the
literature, the chemistry of erythralosamine has been given
little attention presumably because of its low antibacterial
of chemical modifications to improve its physicochemical
properties and activity profiles. Gradually, all positions in
the macrolactone ring and in the ring substituents have
been chemically modified with exception of the 10-methyl
group. The latter is situated at the non-activated C10-carbon
in the macrolide ring. Some modifications in the 10-postion,
however, have been effected by genetic engineering tech-
niques, the products being 10-desmethylerythromycin A,
8
activity in comparison with the parent antibiotic.
The numbering system in erythromycin A and erythralos-
amine is shown in Scheme 1. The basic desosamine sugar
in the erythromycin 5-position is retained under moderate
acidic degradative conditions whereas loss of water and
elimination of the neutral cladinose moiety from the 3-posi-
tion in erythromycin A lead to the formation of the anhydro
spiroketal 2. The spiroketal structure is remarkably stable
4
,5
1
0-ethyl and 10-hydroxy macrolides. Very recently qua-
ternisation at C10 has been effected by intramolecular 1,3-
dipolar cycloaddition in a C10–C11 unsaturated macrolide,
the product being a tricyclic derivative.
6
NMe2
NMe2
O
Br
NMe2
O
O
HO
OH
RO
O
AcO
O
9
3'
O
HO
HO
6
1'
O
O
(i)
O
3
(iii)
O
O
1
2
O
O
OH
OH
O 1
O
1''
O
O
3
''
OH
66%
O
2
3
O
OMe
1
R = H
4 24%
(ii)
R = Ac 84%
Scheme 1. Reagents and reaction conditions: (i) HCl, aq EtOH, rt, 24 h; (ii) Ac
2
O, NEt
3
2 2 2 4
, CH Cl , rt, 2 h; (iii) Br , CCl , rt, 2 h.
Keywords: Chemoselective N-oxidation; Allylic bromination; C10-methyl amination; C10-methyl homologation; Pd-catalysed cross-couplings.
*
Corresponding author. Tel.: +47 22 85 55 21; fax: +47 22 85 55 07; e-mail: kjell.undheim@kjemi.uio.no
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.098

S. Gunnes et al. / Tetrahedron 62 (2006) 6090–6099
6091
chemically, presumably for skeletal structure reasons. The
0-methyl group in erythralosamine is attached to a carbon–
carbon double bond and as such was expected to possess
allylic properties.
For erythralosamine attempts were made to reduce any inter-
0
1
ference from the sugar 2 -hydroxyl group by prior acetyla-
tion. Erythralosamine contains two secondary hydroxyl
groups, which are located in different chemical environ-
0
dimethylamino substituent, which may interact with the
acylating agent to promote ester formation. Hence the 2 -
ments. The desosamine 2 -hydroxyl group is vicinal to the
0
2
. Results and discussion
hydroxyl group reacted more readily than the 3-hydroxyl
group in the macrolide skeleton with acetic anhydride and
triethylamine in dichloromethane, the product being the
This report describes some chemoselective transformations
of the 10-methyl group in erythralosamine derivatives.
Before working with erythralosamine as substrate for chem-
ical transformations, the structure that had been assigned to
erythralosamine, was ascertained by an X-ray analysis. The
ORTEP plot of a single crystal X-ray analysis of erythralos-
amine is shown in Figure 1.
0
10
2 O-acetyl derivative 3. The subsequent reaction with bro-
mine in carbon tetrachloride provided the C8-brominated
structure 4 in low yield (24%) (Scheme 1). The NMR spec-
trum confirmed C8 bromination. The chemical shift for the
carbon signal at C8 was moved from 39 to 70 ppm due to
the deshielding from the bromine. The chemical shift for
the C8-methyl group was also changed from 11 to 27 ppm.
Dept 135 experiments showed C8 to be a quaternary carbon.
7
Erythralosamine (2) was prepared from erythromycin A by
HCl induced transformation in aqueous ethanol (Scheme 1).
Subsequently, bromination was attempted. With bromine in
carbon tetrachloride, a complex reaction mixture resulted.
For comparison, erythronolide B is brominated, with
molecular bromine, adjacent to the 9-carbonyl group in
1
A singlet at 1.74 ppm in the H NMR spectrum for the
methyl group at C8 indicated the same result. Only one stereo-
isomer was obtained, most likely the (8S)-stereoisomer by
analogy to bromination of erythronolide B in the 8-position
9
9
the 8-position.
by NBS in acetic acid. In the reaction between erythralos-
amine and NBS in acetic acid, NMR analysis of the crude
reaction product mixture showed the presence of the
10-bromomethyl derivative as a major component and N-de-
methylated derivatives as minor components. N-Demethyla-
tion reactions were to be expected since demethylation
reactions had been reported for erythromycin ketolides
1
1
when reacted with N-iodosuccinimide, and under other
reaction conditions between halogens and macrolides.
1
2
The demethylation reactions presumably proceed via an
N-bromo-ammonium intermediate with elimination of the
iminium ion, which is further hydrolysed.
The demethylation indicates interaction between the amino
nitrogen and the bromine electrophile. Attempts were there-
fore made to reduce or exclude this interaction by initial con-
struction of the N-oxide 5 (Scheme 2). A reaction with
hydrogen peroxide in methanol at room temperature yielded
the N-oxide 5 in almost quantitative yield. No epoxide
Figure 1. ORTEP plot of compound 2. Ellipsoids are shown at 50% proba-
bility. For clarity only the hydrogen atoms at the oxygen and stereogenic
centres are shown.
O
NMe2
HO
O
O
O
O
OH
(
i)
O
NMe2
HO
O
O
9
3
'
5
>95%
O
1
'
O
O
O
NMe2
O
NMe2
O
OH
(
ii)
HO
HO
O
O
1
O
O
O
O
O
O
O
O
(iii)
2
66%
OH
OH
O
O
O
O
6
49%
7 60%
Scheme 2. Reagents and reaction conditions: (i) H
2
O
2
, MeOH, rt, 6–8 h; (ii) MCPBA, CH
2
Cl
2
, reflux, 8 h; (iii) PPh
3
, THF, reflux, 17 h.

6092
S. Gunnes et al. / Tetrahedron 62 (2006) 6090–6099
O
NMe2
O
NMe2
O
NMe2
HO
O
HO
O
HO
O
Br
O
O
O
O
Br
O
O
(
i)
O
O
O
+
OH
OH
OH
O
O
O
60-80%
O
O
O
5
8
9
(
ii)
NMe2
O
NMe2
O
HO
O
HO
O
O
O
O
Br
O
Br
O
+
OH
OH
O
O
86%
O
10
11
3
Scheme 3. Reagents and reaction conditions: (i) NBS, AcOH, rt, 2–3 h; (ii) PPh , THF, reflux, 17 h.
formation was observed in the C10–C11-carbon double
bond in erythralosamine.
With m-chlorobenzoyl peroxide (MCPBA), however, both
N-oxidation and C–C epoxidation resulted, the product
being the epoxide 6. The N-oxide moiety was chemoselec-
tively deoxygenated on treatment of the product 6 with
triphenylphosphine. The resultant epoxide 7 is chemoiso-
meric with the N-oxide 5 (Scheme 2).
When the erythralosamine N-oxide (5) was reacted with
NBS in acetic acid, the major product was the 10-bromo-
methyl derivative 8, and the minor product was the isomeric
1
1-bromo derivative 9 (Scheme 3). No demethylation of the
Figure 2. ORTEP plot of bromo compound 8. For clarity only hydroxyl
hydrogen atoms and hydrogen atoms at the stereogenic centres are shown.
dimethylamino group was observed, nor was bromine intro-
duced into the C8-position. Erythralosamine N-oxide (5)
did not react with bromine in carbon tetrachloride under
the conditions used for the bromination of the amine 3
10 and 11 without any significant reaction at the allylic
bromide positions (Scheme 3).
(
8
Scheme 1). The relative amounts of the two bromo isomers
and 9 varied from equimolar amounts to 1:10 in favour of
the bromomethyl isomer 8. Chromatographic properties
were very similar, but the major product could be isolated
in an isomer pure state for analytical purposes. The product
is formed under conditions normally associated with an ionic
substitution, not an NBS-free radical reaction. The reaction
mechanism has not been studied. We postulate that the
reaction is initiated by an electrophilic addition to the
carbon–carbon double bond whereby the methyl group
becomes activated for proton abstraction. The product is the
Nucleophiles reacting with the isomeric allylic bromides 10
and 11 can add either at the site of the bromine substituent in
isomer 10 in a S 2 reaction, or add to the terminal double
bond in an S 2 reaction in the isomer 11. Both pathways
N
will provide the same product as shown for the 10-amino-
methyl products 12 and 13 (Scheme 4).
N
0
Stille coupling can be effected on the isomeric allylic
bromides 10 and 11 by palladium-catalysis using the tris
(dibenzylideneacetone)dipalladium chloroform complex
[Pd (dba) $CHCl ] together with tri(2-furyl)phosphine
1
1-bromo isomer 9. A subsequent bromine addition and
bromide elimination from C11 provides the bromomethyl
isomer 8. The structure of the N-oxide bromide 8 has been
ascertained by a single crystal X-ray analysis and the
ORTEP plot is shown in Figure 2.
2
3
3
ꢀ
(TFP) in degassed NMP at 80 C. The reaction is exemplified
in Scheme 4 with phenylation, which yielded a benzyl deriv-
ative 15 as the only regioisomeric product.
For the further transformations, the N-oxide protection was
removed by phosphine deoxygenation. Heating the pure iso-
mer 8 or the crude mixture of the bromo isomers 8 and 9
under reflux in THF in the presence of triphenylphosphine,
provided the amine 10 or the isomeric amine derivatives
The N-oxides can be used directly in the cross-coupling re-
action without prior deoxygenation. For the furyl product 16
in Scheme 5, the substrate was the N-oxides 8 and 9. Excess
phosphine was used since 1 M equiv of the phosphine in this
reaction was consumed rapidly in deoxygenation of the

S. Gunnes et al. / Tetrahedron 62 (2006) 6090–6099
6093
NMe2
NMe2
O
HO
HO
O
L
O
Pd
O
Br
O
O
O
L
O
OH
OH
O
O
NMe2
O
(ii)
O
+
O
RHN
14
HO
O
10
(
i)
O
O
NMe2
NMe2
O
HO
HO
O
OH
O
O
O
Ph
O
O
Br
O
O
O
OH
1
1
2 R = CH2Ph 78%
OH
O
3 R = CH CH CH Ph 79%
O
2
2
2
O
1
5 60%
O
1
1
ꢀ
ꢀ
Scheme 4. Reagents and reaction conditions: (i) RNH
2
, DMF, 80 C, 20 h; (ii) PhSnBu , Pd
3
2
(dba)
3
$CHCl
3
, TFP, NMP, 100 C, 20 h.
O
Me2N
HO
NMe2
NMe2
O
O
R
HO
O
HO
O
O
O
O
O
O
Br
O
O
O
(i)
17
ii)
O
(
OH
OH
OH
O
O
O
O
O
O
8
+ 9
16 R = 2-furyl 51%
7 R = EtOC=CH 54%
18 56%
1
2
ꢀ
3 2 3 3
Scheme 5. Reagents and reaction conditions: (i) RSnBu , Pd (dba) $CHCl , TFP, NMP, 70–80 C, 22–24 h; (ii) (a) 1 M HCl, rt, 20 h, (b) heat, THF.
1
3
N-oxide moiety. The remaining phosphine was ligated to the
palladium complex. Tri(2-furyl)phosphine was the preferred
ligand in these reactions. The ethoxyvinyl derivative 17 was
formed from the N-oxide substrate mixture in the same man-
ner. Only one cross-coupled isomer was obtained from the
allylic bromide mixtures. Rationalisation is that the same
oxo-carbon in the C NMR spectrum was at 207.5 ppm,
and in the minor conjugated ketone isomer at 199.5 ppm.
A new signal at 40.3 ppm appeared in Dept 135 experiments
due to the methylene carbon at C11. The NMR experiments
indicated a migration of the double bond into conjugation
with the carbonyl group and hence formation of an a,b-
unsaturated ketone. The NMR spectrum was only partly
resolved due to the mixture of the two products. When the
product mixture was heated in THF for 2 h, equimolar
amounts of the double bond isomers were present.
3
h -allylpalladium complex 14 (Scheme 4) is formed from
either allylic bromide. The nucleophile would add prefera-
bly to the sterically less shielded position, which is at the
methylene carbon attached to the 10-position.
Tributyl(a-ethoxyvinyl)tin could be used as a masked ke-
tone as shown in Scheme 5. When the coupled product 17
was treated with 1 M HCl in THF, the methyl ketone 18
was obtained in 56% yield. The product was a double
bond isomeric mixture. The endocyclic double bond isomer
was the major product, isomer ratio 3:1 (NMR). This was
verified by high resolution MS, which showed one molecular
ion for the isomeric ketone mixture. The signal for the
Alanes are effective donors of an alkyl group to Pd(II) after
the palladium insertion into a carbon–halogen bond. The use
of an alane reactant required protection of the 2 - and 3-hy-
droxyl groups. TBDMS-triflate was used for disilylation. In
this case isomer pure allyl bromide 10 was used to provide
the disiloxy derivative 19 in a 73% yield (Scheme 6). The
transfer of a methyl group from trimethylaluminium was
effected by Pd-catalysis in NMP when the 10-ethyl
0
NMe2
NMe2
TBDMSO
TBDMSO
O
Et
O
O
Br
O
O
(i)
O
(
ii)
O
10
O
OTBDMS
OTBDMS
O
O
O
O
20 84%
19 73%
ꢀ ꢀ
2 2 3 2 3 3
, CH Cl , 0 C–rt, 17 h; (ii) AlMe , Pd (dba) $CHCl , TFP, NMP, 100 C, 24 h.
Scheme 6. Reagents and reaction conditions: (i) TBDMS-triflate, NMe
3

6094
S. Gunnes et al. / Tetrahedron 62 (2006) 6090–6099
erythralosamine 20 was isolated in 84% yield. Preliminary
experiments with the same catalyst system in THF did not
result in any coupling reaction.
of different molecules. Some additional electron density
was located in a cavity at the four-fold axis, probably from
disordered solvent molecules, this was accounted for by
three dummy carbon atoms in the calculations.
3
. Conclusion
Structural data have been deposited at the Cambridge Crys-
tallographic Data Centre deposition number CCCD 295911
for compound 2, and CCCD 295912 for compound 8.
A method for modification of the chemically stable C10-
methyl group in erythromycine macrolide derivatives is
described. The C10 methyl group is made allylic by acid
catalysed water elimination and acetal formation. The prod-
uct is erythralosamine. Protection by N-oxide formation and
bromination with NBS in acetic acid provided allylic
bromides. Amines were used to effect heteronucleophilic
substitutions. Introduction of carbon substituents were
effected under cross-coupling conditions using Stille reaction
conditions. Under Negishi conditions with trimethylalane
and Pd-catalysis, the 10-ethyl homologue became available.
4
.1.2. Crystal data for C H NO (2). M¼539.69,
2
9
49
8
˚ ˚
monoclinic, P2(1), a¼10.540(1) A, b¼10.797(1) A, c¼
˚
ꢀ
˚
3
1
1
2
3.306(1) A, b¼92.40(1) , V¼1512.8(2) A , Z¼2, D ¼
x
ꢁ ꢁ1
3
.185 Mg m , m¼0.085 mm , T¼105(2) K, measured
ꢀ
7,542 reflections in 2q range 4.8–72.7 , R ¼0.020. Five
int
hundred and thirty-nine parameters refined against 13,651
F , R¼0.037 for I >2s(I ) and 0.051 for all data.
2
o
o
4
6
.1.3. Crystal data for C H BrNO (8)+C H O. M¼
2
9
49
8
x
˚ ˚
4
77.64, tetragonal, I4, a¼b¼21.416(1) A, c¼15.568(1) A,
˚
3
ꢁ3
ꢁ1
V¼7140.3(9) A , Z¼8, D ¼1.261 Mg m , m¼1.203 mm ,
x
T¼105(2) K, measured 50,968 reflections in 2q range 8.3–
4
. Experimental
ꢀ
6
1.0 , R ¼0.030. Six hundred and one parameters refined
int
2
against 10,751 F , R¼0.040 for I >2s(I ) and 0.060 for all
o
o
4
.1. General
data. Absolute structure was determined.
1
7
H NMR spectra were recorded in CDCl at 500 MHz with
3
4.1.4. Erythralosamine (2). A solution of erythromycin A
1
3
Bruker DPX 500 and the C NMR spectra were recorded at
5 MHz. Chemical shifts are reported in parts per million
using CHCl (7.24 ppm) and CDCl (77 ppm) as references.
(6.66 g, 9.10 mmol) in a mixture of EtOH (60 ml) and 10%
HCl (200 ml) was stirred at ambient temperature for 24 h.
The mixture was diluted with ethyl acetate (3ꢂ200 ml),
7
3
3
Mass spectra were recorded at 70 eV. The spectra are pre-
sented as m/z (% relative intensity). Electrospray spectra
were obtained with a Micromass QTOF 2 W spectrometer
with electrospray ionisation quadrupole time of flight. IR
spectra were recorded on a Nicolet Magna FT-IR 550 spec-
trometer using ATR (attenuated total reflectance). Elemental
analyses were performed by Ilse Beetz Mickroanalytisches
laboratorium, Kronach, Germany. Melting points are uncor-
rected.
washed with water (3ꢂ200 ml), dried (MgSO ) and the sol-
4
vent was evaporated. The residual material was subjected
to flash chromatography on silica gel using CH Cl /MeOH/
NH (aq), initially in ratio 90:4:1, then in ratio 90:8:2. (Rf
2
2
3
0.19). The product was a white crystalline solid; yield
ꢀ
7a
ꢀ
3.22 g (66%). Mp 208 C [lit. 207–208 C]; HRMS: [M]
539.3412. Calcd for C H NO : 539.3458; d (500 MHz;
2
9
49
8
H
CDCl ): 0.83 (3H, t, J¼7.3 Hz, 14-CH ), 0.93 (3H, d,
3
3
J¼7.0 Hz, 8-CH ), 1.04 (3H, d, J¼7.3 Hz, 4-CH ), 1.10
3
3
0
(
3H, d, J¼7.4 Hz, 2-CH ), 1.10–1.12 (1H, m, 4 -H ), 1.17
0
3 3
3
a
All reactions were performed under an inert atmosphere
except for the N-oxidations of the macrolides.
(3H, d, J¼6.1 Hz, 5 -CH ), 1.23 (3H, s, 12-CH ), 1.29–
1.36 (1H, m, 14-H ), 1.40 (3H, s, 6-CH ), 1.58 (1H, dd,
a 3
0
J¼13.0, 6.4 Hz, 7-H ), 1.59–1.64 (2H, m, 14-H /4 -H ),
a
b
b
THF was distilled from sodium/benzophenone. Dichloro-
methane and triethylamine were distilled from calcium
hydride. NBS was purified by recrystallisation from water.
Flash chromatography on silica gel was carried out on Merck
kieselgel 60 (230–400).
1.85 (3H, d, J¼1.3 Hz, 10-CH ), 2.23–2.26 (1H, m, 4-H),
3
2.26 (6H, s, N(CH ) ), 2.29–2.34 (1H, pseudo t, J¼13 Hz,
3
2
0
7-H ), 2.44–2.45 (1H, m, 3 -H), 2.44–2.47 (1H, m, 8-H),
b
0
2.71–2.74 (1H, m, 2-H), 3.19 (1H, dd, J¼10.1, 7.3 Hz, 2 -
0
H), 3.40 (1H, d, J¼8.2 Hz, 5-H), 3.44–3.46 (1H, m, 5 -H),
0
4
.16 (1H, d, J¼7.3 Hz, 1 -H), 4.25 (1H, m, 3-H), 4.96 (1H,
4.1.1. X-ray crystallographic analysis for compounds 2
and 8. X-ray data were collected on a Siemens SMART
dd, J¼11.5, 2.8 Hz, 13-H), 5.29 (1H, d, J¼1.4 Hz, 11-H);
d
(75 MHz; CDCl ): 10.3 (14-CH ), 12.0 (8-CH ), 12.6
C
3
3
3
1
3
0
(4-CH ), 13.7 (2-CH ), 14.0 (10-CH ), 21.2 (5 -CH ), 23.1
3 3 3 3
CCD diffractometer using graphite monochromated Mo
˚
0
(12-CH ), 24.4(C-14), 28.9(C-4 ), 29.6(6-CH ),40.1(C-8),
3 3
Ka radiation (l¼0.71073 A). Data collection method:
ꢀ
reduction and cell determination were carried out with the
u-scan, range 0.6 , crystal to detector distance 5 cm. Data
40.4 (N(CH ) ), 42.9 (C-7), 44.5 (C-4), 46.8 (C-2), 65.5 (C-
3 2
0
6), 87.1 (C-5), 88.8 (C-12), 104.5 (C-1 ), 120.0 (C-9), 128.5
0
0
3 ), 69.4 (C-5 ), 70.1 (C-2 ), 71.2 (C-3), 78.9 (C-13), 82.1 (C-
1
3
0
(C-11), 139.2 (C-10), 178.5 (C-1); IR (ATR plate) (CH Cl )
SAINT and XPREP programs. Absorption corrections
were applied by the use of the SADABS program. The
structure was determined and refined using the SHELXTL
program package. The non-hydrogen atoms were refined
with isotropic thermal parameters; hydrogen atoms were lo-
cated from difference Fourier maps and refined with isotropic
thermal parameters.
1
4
2
2
n¼3461 (m), 2971 (s), 2933 (s), 2860 (s), 1727 (s), 1456 (s),
1381 (m), 1373 (m), 1323 (w), 1277 (w), 1171 (s), 1112 (s),
1098 (s), 1073 (s), 1023 (m), 991 (m), 905 (w). MS (EI): 539
(M , 13%), 174 (11), 163 (10), 159 (14), 158 (100), 149 (19),
137 (29), 136 (22), 123 (43), 116 (16), 98 (21), 72 (11).
1
5
+
0
(0.88 ml, 9.30 mmol) and triethylamine (1.29 ml,
In the crystals of the bromo compound 8, a molecule of
methanol was located hydrogen bonded to O(2) and O(8)
4.1.5. 2 O-Acetylerythralosamine (3). Acetic anhydride

S. Gunnes et al. / Tetrahedron 62 (2006) 6090–6099
6095
0
69.2 (C-5 ), 70.7 (C-3), 70.9 (C-2 ), 70.9 (C-8), 79.0
9
(
.30 mmol) were added to a solution of erythralosamine (2)
2.50 g, 4.69 mmol) in CH Cl (15 ml) and the reaction mix-
(N(CH ) ), 43.3 (C-4), 45.7 (C-2), 51.2 (C-7), 62.9 (C-3 ),
3
2
0
0
(C-13), 80.7 (C-6), 88.2 (C-5), 88.8 (C-12), 103.4 (C-1 ),
2
2
0
119.8 (C-9), 132.4 (C-11), 136.6 (C-10), 169.8 (C-2 -
ture was stirred at room temperature for 2 h until TLC mon-
itoring showed full conversion to the product. The reaction
mixture was diluted with ethyl acetate, the solution shaken
with 5% Na CO (aq), with brine, dried (MgSO ) and evapo-
0
OCOCH ), 175.7 (C-1).
3
2
3
4
rated. The residual material was subjected to flash chroma-
tography using silica gel, 90:4:1 CH Cl /MeOH/NH (aq);
4.1.7. Erythralosamine N-oxide (5). Hydrogen peroxide
(30%, 1 ml) was added to a solution of erythralosamine (2)
(1.40 g, 2.52 mmol) in methanol (10 ml) and the reaction
mixture was stirred at ambient temperature for 7 h. Saturated
aqueous sodium bisulfite was added slowly to the reaction
mixture to remove excess hydrogen peroxide before extrac-
2
2
3
ꢀ
yield 2.30 g (84%) of a white solid. Mp 153–154 C;
HRMS: [M] 581.3554. Calcd for C H NO : 581.3564;
3
1
51
9
dH (500 MHz; CDCl ): 0.82 (3H, t, J¼7.1 Hz, 14-CH ),
3
3
0
2
1
6
.91–0.93 (6H, m, 8-CH /4-CH ), 1.08 (3H, d, J¼7.3 Hz,
0
3 3
3
3
-CH ), 1.17 (3H, d, J¼6.0 Hz, 5 -CH ), 1.23 (3H, s,
tion with chloroform. The dried (MgSO ) chloroform solu-
4
0
2-CH ), 1.31–1.35 (2H, m, 4 -H /14-H ), 1.38 (3H, s,
a
tion was evaporated. The residual material was the title
compound that was sufficiently pure for use in the sub-
sequent reaction. The product was a white crystalline solid,
3
a
-CH ), 1.54 (1H, dd, J¼12.0, 5.5 Hz, 7-H ), 1.57–1.65
3
a
0
1H, m, 14-H ), 1.67–1.69 (1H, m, 4 -H ), 1.76 (3H, d,
b b
(
0
ꢀ
J¼1.0 Hz, 10-CH ), 2.03 (3H, s, 2 -OCOCH ), 2.14–2.18
yield 1.4 g (95%), mp 153–155 C. HRMS: [M+1]
556.3484. Calcd for C H NO : 556.3480; d (500 MHz;
3
3
(
1H, m, 4-H), 2.25 (6H, s, N(CH ) ), 2.35–2.40 (1H, pseudo
3
2
29 50
9
H
t, J¼12.1 Hz, 7-H ), 2.38–2.42 (1H, m, 8-H), 2.52–2.57 (1H,
CDCl ): 0.82 (3H, t, J¼7.2 Hz, 13-CH ), 0.92 (3H, d,
b
3
3
0
m, 2-H), 2.68 (1H, dt, J¼11.0, 3.0 Hz, 3 -H), 3.34 (1H, d,
J¼7.0 Hz, 8-CH ), 1.04 (3H, d, J¼7.2 Hz, 4-CH ), 1.10
0
3 3
3
3
0
J¼9.5 Hz, 5-H), 3.40–3.47 (1H, m, 5 -H), 4.18 (1H, m,
(3H, d, J¼7.4 Hz, 2-CH ), 1.22 (3H, d, J¼6.2 Hz, 5 -CH ),
0
3 a a
0
3
8
-H), 4.23 (1H, d, J¼7.5 Hz, 1 -H), 4.78 (1H, dd, J¼10.5,
1.23 (3H, s, 12-CH ), 1.32–1.34 (2H, m, 4 -H /14-H ),
0
.0 Hz, 2 -H), 4.97 (1H, dd, J¼11.5, 2.8 Hz, 13-H), 5.48
1.41 (3H, s, 6-CH ), 1.55 (1H, dd, J¼13.0, 6.4 Hz, 7-H ),
3
a
(
(
(
(
(
6
1H, d, J¼1.5 Hz, 11-H); d (75 MHz; CDCl ): 10.2
1.57–1.62 (1H, m, 14-H ), 1.84 (3H, d, J¼1.1 Hz, 10-
C
3
b
0
14-CH ), 11.2 (8-CH ), 11.8 (4-CH ), 13.7 (2-CH ), 14.3
CH ), 1.90–1.93 (1H, m, 4 -H ), 2.25–2.27 (1H, m, 4-H),
3
3
3
3
3
b
0
0
10-CH3), 21.0 (2 -OCOCH ), 21.3 (5 -CH ), 23.3
12-CH ), 24.3 (C-14), 30.5 (6-CH ), 31.0 (C-4 ), 39.9
C-8), 40.7 (N(CH ) ), 42.7 (C-7), 44.9 (C-4), 46.8 (C-2),
2.27–2.33 (1H, pseudo t, J¼13 Hz, 7-H ), 2.44–2.47 (1H,
3
3
b
0
m, 8-H), 2.65–2.68 (1H, m, 2-H), 3.16 (3H, s, NCH ), 3.17
3
3
3
0
(3H, s, NCH ), 3.34–3.38 (1H, m, 3 -H), 3.39 (1H, d,
3
3
2
0
0
0
0
5.1 (C-3 ), 69.0 (C-5 ), 70.7 (C-2 ), 71.0 (C-3), 78.9
J¼8.2 Hz, 5-H), 3.55–3.59 (1H, m, 5 -H), 3.74 (1H, dd,
0
19.9 (C-9), 128.5 (C-11), 139.3 (C-10), 169.7 (C-2 -
0
(
1
C-13), 81.7 (C-6), 86.7 (C-5), 88.7 (C-12), 102.6 (C-1 ),
0
J¼9.8, 7.1 Hz, 2 -H), 4.20 (1H, m, 3-H), 4.26 (1H, d,
0
J¼7.1 Hz, 1 -H), 4.95 (1H, dd, J¼11.5, 2.8 Hz, 13-H),
OCOCH ), 177.9 (C-1); IR (ATR plate) (CH Cl ) n¼3477
5.49 (1H, d, J¼1.1 Hz, 11-H); d (75 MHz; CDCl ): 10.7
3
2
2
C
3
(
(
m), 2971 (s), 2933 (s), 2877 (m), 1747 (s), 1731 (s), 1456
m), 1372 (s), 1322 (w), 1236 (s), 1171 (s), 1098 (m),
(14-CH ), 12.2 (4-CH ), 12.4 (8-CH ), 14.4 (10-CH ),
3 3 3 3
0
14.5 (2-CH ), 21.4 (5 -CH ), 23.6 (12-CH ), 24.8 (C-14),
3
3
3
0
C-4), 47.4 (C-2), 52.8 (N-CH ), 59.6 (NCH ), 68.0 (C-5 ),
1
060 (s), 1022 (m), 991 (m), 906 (w).
30.5 (6-CH ), 35.3 (C-4 ), 40.5 (C-8), 43.4 (C-7), 45.1
3
0
71.4 (C-3), 71.9 (C-2 ), 76.9 (C-3 ), 79.2 (C-13), 82.4
(
3
3
0
0.59 ml, 1.20 mmol) was added slowly to a solution of
0
(C-6), 88.2 (C-5), 89.3 (C-12), 104.8 (C-1 ), 120.3 (C-9),
0
4
(
.1.6. 2 O-Acetyl-8-bromoerythralosamine (4). Bromine
0
129.0 (C-11), 139.5 (C-10), 178.9 (C-1); IR (film)
0
2
O-acylated erythralosamine (3) (0.590 g, 1.02 mmol) in
carbon tetrachloride (10 ml). Sodium bicarbonate was added
after 2 h and dichloromethane was used to extract the prod-
uct. The organic phases were washed with brine, dried
(CH Cl ) n¼3397 (m), 2973 (s), 2934 (s), 2877 (m), 1717
2
2
(s), 1456 (m), 1372 (m), 1171 (s), 1112 (m), 1099 (m),
1076 (s), 1064 (s), 1019(s), 993 (s), 906 (m).
(
jected to flash chromatography on silica gel using CH Cl /
MeOH/NH (aq) 90:4:1; yield 0.156 g (24%) of a white
3
MgSO ) and evaporated. The residual material was sub-
4
4.1.8. 10,11-Epoxyerythralosamine N-oxide (6). A solu-
tion of erythralosamine (2) (0.573 g, 1.06 mmol) and
MCPBA (1.66 g, 7.43 mmol) in dichloromethane (20 ml)
was heated under reflux for 4 h, another portion of MCPBA
was added (0.55 g, 3.19 mmol) and the heating continued
for another 4 h. Sodium hydrogen carbonate was added
to the cooled mixture, stirred overnight and extracted with
dichloromethane. The organic phase was washed with
Na SO , brine and dried (MgSO ). The crude product was
2
2
solid. HRMS: [M+1], 660.2729/662.2711. Calcd for
C H BrNO : 660.2741/662.2721; d (500 MHz; CDCl ):
3
1
51
9
H
3
0
4
.81 (3H, t, J¼7.3 Hz, 14-CH ), 0.85 (3H, d, J¼7.1 Hz,
3
-CH ), 1.12 (3H, d, J¼7.2 Hz, 2-CH ), 1.18 (3H, d,
3
3
0
0
J¼5.9 Hz, 5 -CH ), 1.26–1.32 (1H, m, 4 -H ), 1.28 (3H, s,
3
a
1
1
1
2
7
2-CH ), 1.35–1.43 (1H, m, 14-H ), 1.60–1.65 (1H, m,
3 a
0
.74 (3H, s, 8-CH ), 1.78 (3H, s, 10-CH ), 2.03 (3H, s,
4-H ), 1.70–1.72 (1H, m, 4 -H ), 1.72 (3H, s, 6-CH ),
b
b
3
2
3
4
purified by flash chromatography on silica gel using
CH Cl /MeOH 9:1; yield 0.298 g, (49%) of a white crystal-
line material. HRMS: [M+1] 572.3429. Calcd for
3
3
0
-H /N(CH ) ), 2.42–2.45 (1H, m, 2-H), 2.69 (1H, dt,
-OCOCH ), 2.12–2.15 (1H, m, 4-H), 2.24–2.27 (7H, m,
3
2
2
a
3 2
0
J¼11.8, 4.2 Hz, 3 -H), 3.09 (1H, d, J¼16.5 Hz, 7-H ), 3.32
C H NO : 572.3456; d (500 MHz; CDCl ): 0.86 (3H,
29 49
b
10
H
3
0
(
4
1H, d, J¼11.0 Hz, 5-H), 3.43–3.47 (1H, m, 5 -H), 4.09–
t, J¼6.9 Hz, 14-CH ), 1.15 (3H, d, J¼7.2 Hz, 8-CH ), 1.18
3
3
0
0
1.28 (3H, s, 6-CH ), 1.31–1.36 (1H, m, 4 -H ), 1.46–1.49
.11 (1H, m, 3-H), 4.20 (1H, d, J¼7.6 Hz, 1 -H), 4.80 (1H,
(3H, s, 10-CH ), 1.18–1.22 (9H, m, 4-CH /2-CH /5 -CH ),
3
3
3
0
3
0
dd, J¼10.4, 8.2 Hz, 2 -H), 5.07 (1H, d, J¼8.8 Hz, 13-H),
3
a
5
.67 (1H, d, J¼1.5 Hz, 11-H); d (75 MHz; CDCl ): 8.8
(1H, m, 14-H ) 1.51 (1H, dd, J¼12.4, 6.8 Hz, 7-H ), 1.61
C
3
a
a
(
2
(
4-CH ), 10.2 (14-CH ), 14.4 (2-CH ), 14.6 (10-CH ),
3
(3H, s, 12-CH ), 1.64–1.70 (1H, m, 14-H ), 1.90–1.93
3 b
3
3
3
0
C-14), 27.3 (8-CH ), 31.1 (C-4 ), 32.1 (6-CH ), 40.7
0
0
7-H ), 2.45–2.56 (2H, m, 8-H/4-H), 3.04–3.10 (1H, m,
1.0 (5 -CH ), 21.3 (2 -OCOCH ), 23.4 (12-CH ), 24.4
3
(1H, m, 4 -H ), 2.17–2.23 (1H, pseudo t, J¼12.7 Hz,
3
3
b
0
3
3
b

6096
S. Gunnes et al. / Tetrahedron 62 (2006) 6090–6099
ꢀ
2
1
5
7
-H), 3.13 (3H, s, NCH ), 3.16 (3H, s, NCH ), 3.30 (1H, s,
3
material, mp 149–151 C (Found: C, 52.85; H, 7.19. Calcd
for C H BrNO : C, 54.89; H, 7.62%). HRMS: [M+1]
3
0
1-H), 3.37–3.41 (1H, m, 3 -H), 3.48 (1H, d, J¼6.1 Hz,
2
9
49
9
0
-H), 3.56–3.58 (1H, m, 5 -H), 3.65 (1H, dd, J¼9.9,
634.2556. Calcd for C H BrNO : 634.2591; [M+1]
29 50 9
636.2550. Calcd for C H BrNO : 636.2570; dH
29 49 9
0
.2 Hz, 2 -H), 4.03 (1H, pseudo t, J¼5.3 Hz, 3-H), 4.36
0
(1H, d, J¼7.1 Hz, 1 -H), 4.91 (1H, dd, 13-H); d (75 MHz;
CDCl ): 10.1 (14-CH ), 13.8 (8-CH ), 14.6 (2-CH ), 15.1
(500 MHz; CDCl ): 0.84 (3H, t, J¼7.2 Hz, 14-CH ), 0.94
C
3
3
(3H, d, J¼7.2 Hz, 8-CH ), 1.09 (3H, d, J¼7.5 Hz, 4-CH ),
3
3
3
3
3
3
3
0
4.5 (C-14), 25.6 (6-CH ), 34.8 (C-4 ), 39.8 (C-8), 44.1
(
2
(
(
12-CH ), 16.8 (4-CH ), 19.0 (10-CH ), 20.9 (5 -CH ),
3
1.12 (3H, d, J¼7.5 Hz, 2-CH ), 1.25 (3H, d, J¼6.1 Hz,
0 0
3 3 a
3
3
3
0
C-7/C-4), 46.0 (C-2), 52.2 (N-CH ), 59.1 (N-CH ), 63.7
5 -CH ), 1.27 (3H, s, 12-CH ), 1.32–1.36 (2H, m, 4 -H /
3
14-H ), 1.39 (3H, s, 6-CH ), 1.59 (1H, dd, J¼12.6, 6.7 Hz,
3
3
a
3
0
6.1 (C-3 ), 78.7 (C-13), 83.3 (C-12), 83.7 (C-6), 85.2
0
C-11), 65.4 (C-10), 67.7 (C-5 ), 71.3 (C-2 ), 73.5 (C-3),
0
7-H ), 1.61–1.67 (1H, m, 14-H ), 1.95–1.98 (1H, m,
a
b
0
4 -H ), 2.19–2.24 (2H, m, 4-H/7-H ), 2.47–2.50 (1H, m,
b b
7
0
(
C-5), 102.3 (C-1 ), 113.5 (C-9), 178.5 (C-1).
8-H), 3.06–3.08 (1H, m, 2-H), 3.18 (3H, s, NCH ), 3.21
3
3H, s, NCH ), 3.39–3.43 (1H, m, 3 -H), 3.46 (1H, d,
3
0
(
0
4.1.9. 10,11-Epoxyerythralosamine (7). A solution of
10,11-epoxyerythralosamine N-oxide (6) (0.380 g,
0.665 mmol) and triphenylphosphine (0.350 g, 1.33 mmol)
J¼4.2 Hz, 5-H), 3.57–3.60 (1H, m, 5 -H), 3.72 (1H, dd,
0
J¼9.9, 7.2 Hz, 2 -H), 4.00 (1H, dd, J¼13.8, 1.6 Hz,
0
10-CH ), 4.33 (1 H, d, J¼7.1 Hz, 1 -H), 4.37 (1H, dd,
a
in THF (5 ml) was heated at reflux for 17 h. Most of the
THF was removed by distillation, the residual material
extracted into ethyl acetate, the extracts shaken with aqueous
sodium bicarbonate, washed with brine and dried (MgSO4).
The solution was evaporated and the residual material was
subjected to flash chromatography on silica gel using
CH Cl /MeOH/NH 90:8:2; yield 0.216 g (60%) of a white
J¼7.9, 2.9, 3-H), 4.59 (1H, dd, J¼13.7, 1.7 Hz, 10-CH ),
b
4.92 (1H, dd, J¼11.3, 2.9 Hz, 13-H), 6.09 (1H, s, 11-H);
d
(8-CH ), 16.5 (2-CH ), 21.0 (5 -CH ), 22.4 (12-CH ), 24.4
(75 MHz; CDCl ): 10.2 (14-CH ), 12.4 (4-CH ), 12.5
3 3 3
C
0
(C-14), 27.1 (6-CH ), 27.3 (10-CH ), 34.8 (C-4 ), 39.9
3
3
3
3
0
3
2
(C-8), 42.7 (C-7), 42.9 (C-4), 45.4 (C-2), 52.6 (NCH ),
3
0
(C-3 ), 70.0 (C-13), 82.1 (C-6), 88.7 (C-5), 89.6 (C-12),
0
58.9 (NCH ), 67.9 (C-5 ), 71.0 (C-2 ), 71.9 (C-3), 76.4
3
2
2
3
ꢀ
0
crystalline material, mp 191–192 C. HRMS: [M+1]
56.3474. Calcd for C H NO : 556.3480; d (500 MHz;
0
5
102.9 (C-1 ), 119.7 (C-9), 134.0 (C-11), 140.0 (C-10),
2
9
50
9
H
CDCl ): 0.89 (3H, t, J¼7.3 Hz, 14-CH ), 1.16–1.21 (15H,
179.9 (C-1); IR (film) (CH Cl ) n¼3409 (m), 2973 (s),
3
3
2
2
0
m, 4 -H ), 1.31 (3H, s, 6-CH ), 1.49–1.56 (2H, m, 14-H /
m, 8-CH /2-CH /4-CH /10-CH /5 -CH ), 1.22–1.28 (1H,
3
2934 (s), 2877 (m), 1721 (s), 1456 (m), 1374 (m), 1169
(s), 1099 (m), 1060 (s), 1027 (m), 995 (m), 907 (w).
3
3
3
3
0
a
3
a
7
4
-H ), 1.63 (3H, s, 12-CH ), 1.66–1.73 (2H, m, 14-H /
a 3 b
0
-H ), 2.26 (1H, pseudo t, J¼13 Hz, 7-H ), 2.28 (6H, s,
4.1.11. 10-Bromomethyl-10-desmethylerythralosamine
(10). A solution of 10-bromomethyl-10-desmethylerythra-
losamine N-oxide (8) (2.60 g, 0.004 mol) and triphenylphos-
phine (2.20 g, 0.008 mol) in THF (30 ml) was heated under
reflux for 17 h when TLC showed the reaction to be com-
plete. Most of the THF was removed by distillation, the
residual material extracted into ethyl acetate, the extracts
shaken with aqueous sodium bicarbonate, washed with
b
b
N(CH ) ), 2.40–2.45 (1H, m, 4-H), 2.47–2.55 (2H, m,
2
3
0
.4 Hz, 2 -H), 3.13 (1H, s, 11-H), 3.44–3.48 (1H, m, 5 -H),
8
7
3
-H/3 -H), 3.10–3.13 (1H, m, 2-H), 3.15 (1H, dd, J¼10.1,
0
0
.49 (1H, d, J¼5.8 Hz, 5-H), 4.16–4.18 (1H, m, 3-H), 4.26
0
(
1H, d, J¼7.3 Hz, 1 -H), 4.92 (1H, dd, J¼10.7, 3.4 Hz,
1
1
3-H); d (75 MHz; CDCl ): 10.2 (14-CH ), 13.6 (8-CH ),
C 3 3 3
3.7 (2-CH3), 15.2 (12-CH3), 16.7 (4-CH3), 19.1
0
C-4 ), 39.9 (C-8), 40.3 (N(CH ) ), 43.7 (C-4), 44.1 (C-7),
(
(
10-CH ), 21.2 (5 -CH ), 24.5 (C-14), 25.9 (6-CH ), 28.8
3
brine, dried (MgSO ), the solution evaporated and the resid-
4
3
3
0
5.8 (C-2), 63.7 (C-11), 65.5 (C-10), 65.6 (C-3 ), 69.5
ual material subjected to flash chromatography on silica gel
using CH Cl /MeOH/NH 90:8:2; yield 2.13 g (86%) of
3
2
0
C-5 ), 69.7 (C-2 ), 73.2 (C-3), 79.1 (C-13), 83.3 (C-12),
8
4
2
2
3
0
3.7 (C-6), 84.9 (C-5), 102.8 (C-1 ), 113.6 (C-9), 178.9
0
ꢀ
(
a white crystalline material, mp 88–90 C. HRMS: [M+1]
618.2607. Calcd for C H BrNO : 618.2636; [M+1]
0
2
9
49
8
(
2
(
C-1); IR (KBr) (CH Cl ) n¼3460 (m), 2972 (s), 2938 (s),
620.2593. Calcd for C H BrNO : 620.2615; dH
29 49 8
2
2
878 (m), 1726 (s), 1456 (s), 1380 (m), 1328 (w), 1278
w), 1168 (s), 1109 (m), 1048 (s), 994 (m), 974 (w).
(500 MHz; CDCl ): 0.85 (3H, t, J¼7.3 Hz, 13-CH ), 0.93
3
3
(3H, d, J¼7.1 Hz, 8-CH ), 1.09 (3H, d, J¼7.5 Hz, 2-CH ),
0
3 a
3
3
1
.12 (3H, d, J¼7.5 Hz, 4-CH ), 1.17–1.22 (1H, m, 4 -H ),
0
3 3
4
.1.10. 10-Bromomethyl-10-desmethylerythralosamine
1.19 (3H, d, J¼6.1 Hz, 5 -CH ), 1.28 (3H, s, 12-CH ),
N-oxide (8) and isomer (9). A solution of NBS in acetic
acid (15 ml) was added to a solution of erythralosamine
N-oxide (5) (1.56 g, 2.50 mmol) in acetic acid (20 ml) and
the resultant solution was stirred at room temperature for
1.31–1.36 (1H, m, 14-H ), 1.38 (3H, s, 6-CH ), 1.59 (1H,
a 3
0
1.69 (1H, m, 14-H ), 2.13–2.19 (1H, m, 4-H), 2.21–2.25
dd, J¼12.7, 6.6 Hz, 7-H ), 1.62–1.69 (1H, m, 4 -H ), 1.62–
a
b
b
(1H, m, 7-H ), 2.30 (6H, s, N(CH ) ), 2.45–2.52 (1H, m,
b
3 2
0
3
h when TLC showed the reaction to be complete. Most
8-H), 2.45–2.52 (1H, m, 3 -H), 3.08 (1H, dq, J¼7.4,
0
of the acetic acid was removed under reduced pressure and
aqueous potassium hydroxide was added to the reaction mix-
ture until pH 9–11. The product was extracted into chloro-
form that was washed and dried (MgSO ) before the
4
solvent was distilled off. The product was isolated after flash
chromatography on silica gel using CH Cl /MeOH/NH ,
2.6 Hz, 2-H), 3.23 (1H, dd, J¼10.0, 7.6 Hz, 2 -H), 3.45–
0
3.49 (1H, m, 5 -H), 3.48 (1H, d, J¼6.4 Hz, 5-H), 4.00 (1H,
0
d, J¼14.0 Hz, 10-CH ), 4.23 (1H, d, J¼7.4 Hz, 1 -H),
a
4.39–4.41 (1H, m, 3-H), 4.57 (1H, d, J¼14.0 Hz, 10-CH ),
b
4.92 (1H, dd, J¼11.3, 2.7 Hz, 13-H), 6.03 (1H, s, 11-H);
d
(75 MHz; CDCl ): 10.3 (14-CH ), 12.2 (4-CH ), 12.5
3 3 3
2
2
3
C
initially in ratio 9:1:0.1, and then 9:2:0.1; yield 0.95 g
60%). The product was a mixture of the bromo regio-
(8-CH ), 16.6 (2-CH ), 21.3 (5-CH ), 22.4 (12-CH ), 24.5
3 3 3 3
0
(C-14), 27.1 (10-CH ), 27.2 (6-CH ), 28.9 (C-4 ), 39.9
2 3
(
isomers 8 and 9 with very similar chromatographic proper-
ties. The major isomer 8 was obtained in isomerically pure
state, after repeated chromatography, as a white crystalline
(C-8), 40.4 (N(CH ) ), 42.9 (C-7/C-4), 45.3 (C-2), 65.4
3 2
(C-3 ), 69.6 (C-5 ), 69.7 (C-2 ), 71.9 (C-3), 79.2 (C-13),
0
0
82.2 (C-6), 86.0 (C-5), 89.6 (C-12), 103.2 (C-1 ), 119.7
0
0

S. Gunnes et al. / Tetrahedron 62 (2006) 6090–6099
6097
(
C-9), 134.0 (C-11), 140.2 (C-10), 179.7 (C-1); IR (film,
(0.439 g, 79%) of a white crystalline solid, mp 139–
140 C (EtOAc/hexane) (Found: C, 67.56; H, 9.12. Calcd
ꢀ
for C H N O : C, 67.83; H, 8.99%). HRMS [H ]: M
CH Cl ) n¼3467 (m), 2973 (s), 2936 (s), 2877 (m), 1720
2
2
+
(
(
s), 1456 (s), 1380 (s), 1315 (w), 1277 (w), 1170 (s), 1099
s), 1074 (s), 1049 (s), 1027(s), 993 (m), 907 (m).
3
8 60 2 8
673.4422. Calcd for C H N O : 673.4422; dH
3
8 61 2 8
(
500 MHz; CDCl ): 0.84 (3H, t, J¼7.3 Hz, 14-CH ), 0.92
3
3
4
.1.12. 10-Bromomethyl-10-desmethylerythralosamine
10) and isomer (11). Deoxygenation of the crude mixture
of 10-bromomethyl-10-desmethylerythralosamine N-oxide
8) and isomer (9) was effected as above to provide 10-
bromomethyl-10-desmethylerythralosamine (10) and isomer
11) as a mixture reflecting the ratio in the isomeric sub-
strate.
(3H, d, J¼7.1 Hz, 8-CH ), 1.07–1.10 (6H, m, 4-CH /
0
3 3
3
3
(
2-CH ), 1.18 (3H, d, J¼6.9 Hz, 5 -CH ), 1.20–1.25 (1H,
0
a 3 a
m, 4 -H ), 1.26 (3H, s, 12-CH ), 1.29–1.35 (1H, m, 14-H ),
(
1.39 (3H, s, 6-CH ), 1.56 (1H, dd, J¼12.6, 6.5 Hz, 7-H ),
0
b b
3
a
1.61–1.66 (2H, m, 14-H /4 -H ), 1.82–1.91 (2H, m,
(
PhCH CH CH N), 2.14–2.16 (1H, m, 4-H), 2.21–2.27
2 2 2
(1H, pseudo t, J¼13.5 Hz, 7-H ), 2.28 (6H, s, N(CH ) ),
b
3 2
0
PhCH CH CH N), 3.22–3.26 (2H, m, 2 -H/10-CH ), 3.43–
2
.46–2.52 (2H, m, 8-H/3 -H), 2.64–2.77 (5H, m, 2-H/
0
4
.1.13. 10-Benzylaminomethyl-10-desmethylerythralos-
amine (12). A solution of the crude isomeric mixture of
0-bromomethyl-10-desmethylerythralosamine (10) and
2
2
2
0
a
3.47 (1H, m, 5 -H), 3.50 (1H, d, J¼6.1 Hz, 5-H), 3.59 (1H,
0
1
d, J¼16.3 Hz, 10-CH ), 4.21 (1H, d, J¼7.5 Hz, 1 -H), 4.35
b
isomer (11) (0.502 g, 0.812 mmol), and benzylamine
ꢀ
(1H, m, 3-H), 4.94 (1H, dd, J¼11.4, 2.7 Hz, 13-H), 5.68
(
0.35 ml, 3.25 mmol) in DMF (4 ml) was heated at 60 C
(1H, d, 11-H); d (75 MHz; CDCl ): 10.4 (14-CH ), 12.4
3
C
3
0
(12-CH ), 24.4 (C-14), 28.0 (6-CH ), 29.3 (C-4 ), 31.5
for 16 h. Water was added to the cold reaction mixture, the
mixture extracted with ethyl acetate, the extracts shaken
with aqueous sodium hydrogen carbonate, with brine, dried
(8-CH ), 13.2 (2-CH ), 14.9 (4-CH ), 21.2 (5 -CH ), 22.9
3
3
3
3
0
(PhCH CH CH N), 33.8 (PhCH CH CH N), 40.4 (C-8),
3
3
2
2
2
2
2
2
(
MgSO ) and the solvent distilled off. The residual material
4
40.5 (N(CH ) ), 43.2 (C-7), 44.0 (C-4), 46.3 (10-CH ),
3 2 2
0
46.6 (C-2), 48.6 (PhCH CH CH N), 65.3 (C-3 ), 69.5
2 2 2
was subjected to flash chromatography on silica gel using
CH Cl /MeOH/NH (aq) 90:8:2; yield 0.410 g (78%) of
a white solid. HRMS: [M+1] 645.4102. Calcd for
0
0
(C-5 ), 70.4 (C-2 ), 71.3 (C-3), 79.1 (C-13), 82.2 (C-6),
85.6 (C-5), 89.3 (C-12), 103.6 (C-1 ), 120.0 (C-9), 125.7
2
2
3
0
(Ar), 128.3 (Ar/C-11), 142.0 (Ar/C-10), 178.9 (C-1); IR
C H N O : 645.4109; d (500 MHz; CDCl ): 0.85 (3H,
3
6
57
2
8
H
3
t, J¼7.3 Hz, 14-CH ), 0.88 (3H, d, J¼7.0 Hz, 8-CH ), 1.05
(film) (CH Cl ) n¼3418 (m), 2970 (s), 2933 (s), 2876 (w),
3
3
2
2
(
3H, d, J¼7.4 Hz, 4-CH ), 1.08 (3H, d, J¼7.4 Hz, 2-CH ),
1716 (s), 1456 (m), 1374 (m), 1170 (s), 1111 (s), 1096 (s),
1073 (s), 1049 (s), 1025 (s), 994 (m), 904 (w).
3
3
0
.26 (3H, s, 12-CH ), 1.35–1.42 (1H, m, 14-H ), 1.39 (3H,
0
1
1
.17 (3H, d, J¼6.2 Hz, 5 -CH ), 1.21–1.23 (1H, m, 4 -H ),
3
a
3
a
s, 6-CH ), 1.55 (1H, dd, J¼12.7, 6.2 Hz, 7-H ), 1.62–1.68
4.1.15. 10-Benzyl-10-desmethylerythralosamine (15). A
solution of a crude isomeric mixture of 10-bromomethyl-
10-desmethylerythralosamine (10) and isomer (11)
(0.280 g, 0.453 mmol) in NMP (5 ml) was degassed
and tris(2-furyl)phosphine (0.025 g, 0.109 mmol) and
Pd (dba) $CHCl (0.014 g, 0.014 mmol) were added. The
3
a
0
2H, m, 4 -H /14-H ), 2.16–2.20 (1H, m, 4-H), 2.22–2.26
b b
(
(
8
2
1H, m, 7-H ), 2.29 (6H, s, N(CH ) ), 2.45–2.52 (2H, m,
b 3 2
0
-H/3 -H), 2.76–2.82 (1H, m, 2-H), 3.27–3.32 (2H, m,
-H/10-CH ), 3.42–3.48 (1H, m, 5 -H), 3.46 (1H, d,
0
0
a
J¼6.7 Hz, 5-H), 3.63 (1H, d, J¼16.3 Hz, 10-CH ), 3.82
b
2
3
3
ꢀ
(
1H, d, J¼13.2 Hz, CH Ph), 3.92 (1H, d, J¼13.2 Hz,
reaction mixture was heated at 50 C for 10 min before tri-
butyl(phenyl)stannane (0.30 ml, 0.906 mmol) was added.
a
0
CH Ph), 4.20 (1H, d, J¼7.2 Hz, 1 -H), 4.31–4.33 (1H, m,
b
ꢀ
3
1
1
2
-H), 4.96 (1H, dd, J¼11.4, 2.7 Hz, 13-H), 5.77 (1H, s,
The reaction mixture was then heated at 100 C for 20 h.
1-H); d (75 MHz; CDCl ): 10.3 (14-CH ), 12.3 (8-CH ),
C
The cold reaction mixture was extracted into ethyl acetate,
the solution shaken with aqueous sodium hydrogen carbon-
ate, with brine, dried (MgSO ) and the solvents distilled off
3
3
3
0
4.4 (C-14), 28.3 (6-CH ), 29.4 (C-4 ), 40.3 (C-8), 40.5
3.3 (2-CH ), 14.3 (4-CH ), 21.2 (5 -CH ), 23.0 (12-CH ),
3
3
3
3
0
3
4
(
(
7
N(CH ) ), 43.1 (C-7), 44.2 (C-4), 45.7 (10-CH ), 46.6
2
C-2), 52.7 (CH Ph), 65.3 (C-3 ), 69.4 (C-5 ), 70.1 (C-2 ),
2
at reduced pressure. The residual material was subjected to
flash chromatography on silica gel using CH Cl /MeOH/
NH (aq) 90:4:1, and then ratio 9:2:1; yield 0.168 g (60%)
3
2
0
1.1 (C-3), 79.1 (C-13), 82.2 (C-6), 85.9 (C-5), 89.3
0
0
2
2
3
0
(
(
C-12), 103.8 (C-1 ), 120.0 (C-9), 126.8 (Ar), 128.0
C-11), 128.1 (Ar), 128.4 (Ar), 140.3 (Ar), 141.9 (C-10),
of a white crystalline material. HRMS: [M+1] 616.3847.
Calcd for C H NO : 616.3843; d (500 MHz; CDCl3):
3
5
54
8
H
1
2
78.9 (C-1); IR (film) (CH Cl ) n¼3454 (m), 2972 (s),
0.79 (3H, t, J¼7.3 Hz, 14-CH ), 1.06 (3H, d, J¼6.9 Hz,
2
2
3
0
934 (s), 2876 (m), 1722 (s), 1455 (s), 1380 (m), 1323
8-CH ), 1.08–1.11 (1H, m, 4 -H ), 1.13 (3H, d, J¼7.5 Hz,
3
a
(
(
w), 1278 (w), 1171 (s), 1111 (s), 1097 (s), 1074 (s), 1049
s), 1025 (s), 993 (m), 905 (m).
4-CH ), 1.15 (3H, d, J¼8.2 Hz, 2-CH ), 1.17 (3H, d,
0
3 b
3
3
J¼6.5 Hz, 5 -CH ), 1.15–1.18 (1H, m, 14-H ), 1.19 (3H, s,
1
2-CH ), 1.43 (3H, s, 6-CH ), 1.50–1.55 (1H, m, 14-H ),
3 3 b
0
1.56–1.65 (2H, m, 7-H /4 -H ), 2.12 (6H, s, N(CH ) ),
a b 3 2
4.1.14. 10-(3-Phenylprop-1-ylaminomethyl)-10-des-
methylerythralosamine (13). A solution of the crude isomeric
2.26–2.31 (1H, m, 4-H), 2.40 (1H, pseudo t, J¼13.0, 7-H ),
b
0
mixture of 10-bromomethyl-10-desmethylerythralosamine
(
2.46–2.51 (1H, m, 3 -H), 2.52–2.59 (1H, m, 8-H), 3.01
0
10) and isomer (11) (0.406 g, 0.653 mmol) together with
-phenylpropylamine (0.37 ml, 2.63 mmol) in DMF was
(1H, dd, J¼9.5, 8.0 Hz, 2 -H), 3.14–3.21 (1H, m, 2-H),
0
3
3.26 (1H, d, J¼17.5 Hz, 10-CH Ph), 3.41–3.45 (1H, m, 5 -
a
ꢀ
heated to 60 C for 17 h. Water was added to the cold reac-
tion mixture, the mixture extracted with ethyl acetate, the
extracts shaken with aqueous sodium hydrogen carbonate,
with brine, dried (MgSO ) and the solvent distilled off.
4
The residual material was subjected to flash chromatography
on silica gel using CH Cl /MeOH/NH (aq) 90:8:2; yield
H), 3.50 (1H, d, J¼5.0 Hz, 5-H), 4.00 (1H, d, J¼17.5 Hz,
0
10-CH Ph), 4.21 (1H, d, J¼3.66 Hz, 1 -H), 4.36–4.38 (1H,
b
m, 3-H), 4.91 (1H, dd, J¼10.9, 1.7 Hz, 13-H), 5.07 (1H, s,
11-H), 7.17–7.22 (1H, m, Ar), 7.26–7.30 (4H, m, Ar); dC
(75 MHz; CDCl ): 10.3 (14-CH ), 12.3 (8-CH ), 12.7
3
3
3
0
(2-CH ), 15.7 (4-CH ), 21.2 (5 -CH ), 22.8 (12-CH ), 24.3
3
2
2
3
3
3
3

6098
S. Gunnes et al. / Tetrahedron 62 (2006) 6090–6099
0
(
N(CH ) ), 43.1 (C-7), 43.6 (C-4), 45.9 (C-2), 65.3 (C-3 ),
6
(
1
C-14), 27.6 (6-CH ), 29.2 (C-4 ), 33.0 (10-CH ), 40.2 (C-8/
0
(3H, d, J¼3.2 Hz, 4-CH ), 1.09 (3H, d, J¼3.0 Hz, 2-CH ),
0 0
3 a
3
2
3
3
1.19 (3H, d, J¼6.2 Hz, 5 -CH ), 1.21–1.22 (1H, m, 4 -H ),
3 2 3
3
2
0
C-6), 86.4 (C-5), 89.4 (C-12), 103.3 (C-1 ), 120.3 (C-9),
0
9.4 (C-5 ), 69.6 (C-2 ), 71.9 (C-3), 79.3 (C-13), 82.0
1.24 (3H, s, 12-CH ), 1.27 (3H, t, J¼7.1 Hz, OCH CH ),
a 3
0
26.0 (Ar), 128.3 (Ar), 129.4 (C-11), 129.5 (Ar), 140.1
1.28–1.32 (1H, m, 14-H ), 1.40 (3H, s, 6-CH ), 1.56 (1H,
dd, J¼12.6, 6.5 Hz, 7-H ), 1.60–1.66 (1H, m, 4-H), 1.60–
a
(
Ar), 144.5 (C-10), 179.5 (C-1); IR (film) (CH Cl )
2
1.66 (1H, m, 14-H ), 2.26–2.30 (1H, m, 4-H), 2.26–2.30
b
2
v¼3467 (br), 2972 (s), 2934 (m), 2876 (w), 1719 (s), 1455
(1H, m, 7-H ), 2.30 (6H, s, N(CH ) ), 2.42–2.55 (1H, m,
b
3 2
0
(
m), 1379 (m), 1321 (w), 1274 (w), 1169 (s), 1111 (m),
097 (m), 1073 (s), 1050 (s), 1023(s), 992 (m), 906 (w).
8-H), 2.42–2.54 (1H, m, 3 -H), 2.77 (1H, dd, J¼17.0,
1
1.8 Hz, 10-CH ), 3.01 (1H, dq, J¼7.5, 3.5 Hz, 2-H), 3.24
a
0
(
1H, dd, J¼10.1, 7.4 Hz, 2 -H), 3.41 (1H, d, J¼17.0 Hz,
0
4
.1.16. 10-(2-Furyl)methyl-10-desmethylerythralos-
10-CH ), 3.41–3.45 (1H, m, 5 -H), 3.48 (1H, d, J¼5.5 Hz,
b
amine (16). A solution of the crude isomeric mixture
of 10-bromomethyl-10-desmethylerythralosamine N-oxide
5-H), 3.70–3.78 (1H, m, OCH CH ), 3.97 (1H, d,
3
2
J¼1.1 Hz, C]CH ), 4.04 (1H, s, C]CH ), 4.20 (1H,
a
b
0
(
8) and isomer (9) (0.196 g, 0.310 mmol) in NMP (3 ml)
was degassed and tris(2-furyl)phosphine (0.018 g,
.077 mmol) and Pd (dba) $CHCl (0.010 g, 0.010 mmol)
d, J¼6.8 Hz, 1 H), 4.36–4.38 (1H, m, 3-H), 4.91 (1H, dd,
J¼11.1, 2.9 Hz, 13-H), 5.55 (1H, s, 11-H); d (75 MHz;
C
0
CDCl ): 10.3 (14-CH ), 12.3 (8-CH ), 12.7 (4-CH ), 14.4
2
3
3
3
3
3
3
ꢀ
0
(OCH CH ), 15.4 (2-CH ), 21.2 (5 -CH ), 22.8 (12-CH ),
2 3 3 3 3
were added. The reaction mixture was heated at 50 C
for 10 min and more tris(2-furyl)phosphine (0.12 ml,
0
24.5 (C-14), 27.9 (6-CH ), 29.8 (C-4 ), 33.4 (10-CH ),
3
2
0
.372 mmol) was added. The reaction mixture was heated
ꢀ
40.3 (C-8), 40.5 (N(CH ) ), 43.2 (C-7/C-4), 45.9 (C-2),
3 2
0 0 0
62.9 (OCH CH ), 64.8 (C-3 ), 69.4 (C-5 ), 70.1 (C-2 ),
2 3
at 80 C for 22 h. The product was extracted with ethyl ace-
tate, the organic phase washed with aqueous sodium hydro-
gen carbonate, brine and dried (MgSO ). The NMP was
removed under reduced pressure and the residual material
subjected to flash chromatography on silica gel using
CH Cl /MeOH/NH (aq) 90:4:1, yield 0.095 g (51%) of
71.7 (C-3), 79.1 (C-13), 82.1 (C-6), 83.1 (]CH ), 85.9
2
0
(C-11), 140.5 (C-10), 161.1 (EtOCR]CH ), 179.5 (C-1).
(C-5), 89.3 (C-12), 103.3 (C-1 ), 120.4 (C-9), 128.4
4
2
4.1.18. 10-(2-Oxopropyl)-10-desmethylerythralosamine
(18). 10-(2-Ethoxyprop-2-en-1-yl)methyl-10-desmethylery-
thralosamine (17) (0.180 g, 0.295 mmol) was dissolved in
THF (1.5 ml) and 1 M HCl (0.30 ml) was added. The reac-
tion mixture was stirred for 20 h at room temperature.
2
2
3
a white solid; dH (500 MHz; CDCl ): 0.75 (3H, t,
3
J¼7.3 Hz, 14-CH ), 0.92 (3H, d, J¼6.9 Hz, 8-CH ), 1.02–
3
3
0
CH ), 1.18 (3H, s, 12-CH ), 1.35 (3H, s, 6-CH ), 2.16 (6H,
1
.05 (6H, m, 4-CH /2-CH ), 1.12 (3H, d, J¼6.1 Hz, 5 -
3
3
3 3 3
s, N(CH ) ), 2.92–3.00 (1H, m, 2-H), 3.07 (1H, dd,
3
NaHCO was added to the reaction mixture and the mixture
3
2
0
J¼10.4, 7.4 Hz, 2 -H), 3.32 (1H, dd, J¼18.1, 1.3 Hz,
extracted with ethyl acetate, washed with brine and dried
(MgSO ). The product was isolated as a white solid
1
0-CH ), 3.42 (1H, d, J¼5.6 Hz, 5-H), 3.86 (1H, d,
a
4
0
J¼18.2 Hz, 10-CH ), 4.14 (1H, d, J¼7.4 Hz, 1 -H), 4.28–
0.120 g (56%) after flash chromatography on silica gel using
CH Cl /MeOH 9:1, then ratio 9:2. HRMS: [M+1] 582.3646.
b
4
.32 (1H, m, 3-H), 4.85 (1H, dd, J¼10.9, 2.6 Hz, 13-H),
2
2
5
.36 (1H, s, 11-H), 6.10–6.11 (1H, m, furan), 6.24–6.25
1H, m, furan), 7.25–7.26 (1H, m, furan); dC (75 MHz;
Calcd for C H NO : 582.3636; d (500 MHz; CDCl3):
31 52 9 H
(
CDCl ): 10.2 (14-CH ), 12.1, 12.7, 15.1, 21.1, 22.6, 24.2,
0.84 (3H, t, J¼7.2 Hz, 14-CH ), 0.90 (3H, d, J¼7.0 Hz,
3
8-CH ), 1.27 (3H, s, 12-CH ), 1.40 (3H, s, 6-CH ), 2.27
3
3
3
3
3
2
4
(
8
1
6.3, 27.8, 29.0, 40.0 (C-8), 40.2 (N(CH ) ), 43.0 (C-7),
3
(6H, s, N(CH ) ), 3.00 (1H, dd, J¼16.8, 1.7 Hz, 10-CH ),
2
3 2
a
0
C-2 ), 71.3 (C-3), 78.9 (C-13), 81.9 (C-6), 86.1 (C-5),
0
3.6 (C-4), 45.8 (C-2), 65.0 (C-3 ), 69.3 (C-5 ), 69.8
3.47 (1H, d, J¼4.9 Hz, 5-H), 3.91 (1H, d, J¼16.8 Hz, 10-
0
9.3 (C-12), 103.5 (C-1 ), 106.1 (furan), 110.1 (furan),
0
5.60 (1H, s, 11-H); d (75 MHz; CDCl ): 10.3 (14-CH ),
CH ), 4.23 (1H, d, J¼7.3 Hz, 1 H), 4.94 (1H, dd, 13-H),
b
0
20.1 (C-9), 129.3 (C-11), 140.5/140.9 (C-10/furan), 153.7
C
3
3
0
22.5 (12-CH ), 24.5 (C-14), 27.3 (6-CH ), 28.7 (C-4 ),
12.4 (8-CH ), 12.5 (4-CH ), 16.0 (2-CH ), 21.2 (5 -CH ),
3
3
3
3
0
(
furan), 179.2 (C-1).
3
3
2
9.3 (10-CH COCH ), 40.3 (C-8/(N(CH ) )), 42.3/43.3/
2 3 3 2
0
43.6 (C-7/C-4/10-CH COCH ), 45.7 (C-2), 65.7 (C-3 ),
2 3
4
.1.17. 10-(2-Ethoxyprop-2-en-1-yl)methyl-10-desmethyl-
0
0
erythralosamine (17). A solution of a crude isomeric
mixture of 10-bromomethyl-10-desmethylerythralosamine
N-oxide (8) and isomer (9) (0.100 g, 0.158 mmol) was deoxy-
69.6/69.7 (C-5 /(C-2 ), 71.6 (C-3), 79.3 (C-13), 82.1 (C-6),
0
86.0 (C-5), 89.7 (C-12), 103.4 (C-1 ), 120.3 (C-9), 130.1
(C-11), 136.5 (C-10), 179.4 (C-1), 207.5 (10-CH COCH ).
2
3
genated together with tris(2-furyl)phosphine (0.036 g,
ꢀ
7 h. The catalyst Pd (dba) $CHCl (0.005 g, 0.005 mmol)
0
0
1
.158 mmol) in NMP (1 ml) and was heated at 70 C for
4.1.19. 10-Bromomethyl-2 O,3O-bis(tert-butyldimethyl-
silyl)-10-desmethylerythralosamine (19). A solution of
10-bromomethyl-10-desmethylerythralosamine (10) (0.250 g,
0.404 mmol) and trimethylamine (0.17 ml, 1.21 mmol) in
2
3
3
and tris(2-furyl)phosphine (0.009 g, 0.038 mmol) were
added to the reaction mixture together with tributyl(1-ethoxy-
ethenyl)stannane (0.064 ml, 0.189 mmol). The resultant
ꢀ
CH Cl (5 ml) was cooled to 0 C and TBDMS-triflate
2
2
ꢀ
mixture was heated at 70 C for 24 h. The solvent was re-
(0.23 ml, 1.21 mmol) added dropwise to the reaction mix-
ture. Water was added to the cold reaction mixture after
17 h, the mixture extracted with ethyl acetate, the extracts
shaken with aqueous sodium hydrogen carbonate, with
moved at reduced pressure, the residue extracted into ethyl
acetate, the solution shaken with aqueous sodium hydrogen
carbonate, with brine, dried (MgSO ), evaporated and the re-
4
sidual material subjected to flash chromatography on silica
gel CH Cl /MeOH/NH (aq) 90:4:1; yield 0.052 g (54%)
of a white material. HRMS: [M+1], 610.3948. Calcd for
brine, dried (MgSO ) and the solvent distilled off. The resi-
4
dual material was subjected to flash chromatography on
silica gel using hexane/Et O 5:1; yield 0.25 g (73%) of
2
2
3
2
C H NO : 610.3949; d (500 MHz; CDCl ): 0.83 (3H, t,
3
a white crystalline solid. HRMS: [M+1], 846.4329. Calcd
for C H NO Si Br: 846.4365; d (500 MHz; CDCl3):
3
56
9
H
3
J¼7.3 Hz, 14-CH ), 0.94 (3H, d, J¼7.1 Hz, 8-CH ), 1.07
3
3
41 77
8
2
H

S. Gunnes et al. / Tetrahedron 62 (2006) 6090–6099
6099
0
.06/0.07/0.19 (4ꢂ3H, 4ꢂs, 2ꢂ(CH ) C(CH ) Si), 0.85
d (75 MHz; CDCl ): ꢁ4.4/ꢁ3.0 ((CH ) C(CH ) Si), 10.4
3 3 3 2 3
3
3
3 2
C
3
3 3
3 2
(
3H, t, J¼7.5 Hz, 14-CH ), 0.89/0.90 (2ꢂ9H, 2ꢂs, 2ꢂ
(14-CH ), 11.7 (4-CH ), 11.9 (8-CH ), 12.5 (10-CH CH ),
3
(
(
CH ) C(CH ) Si), 0.96 (3H, d, J¼7.0 Hz, 8-CH ), 0.94
16.3 (2-CH ), 18.5/18.6 ((CH ) C(CH ) Si), 20.4 (10-
3 3 3 3 2
3
3
3 2
3
0
CH CH ), 21.2 (5 -CH ), 23.4 (12-CH ), 24.2 (C-14),
2 3 3 3
3H, d, J¼7.1 Hz, 4-CH ), 1.06 (3H, d, J¼7.5 Hz, 2-CH ),
3
3
0
.28 (3H, s, 12-CH ), 1.30–1.41 (1H, m, 14-H ), 1.47 (3H,
0
0
26.0/26.3 ((CH ) C(CH ) Si), 29.4 (C-4 ), 30.3 (6-CH ),
3 3 3 2 3
1
1
.14 (3H, d, J¼6.0 Hz, 5 -CH ), 1.16–1.21 (1H, m, 4 -H ),
3
a
40.8 (C-8), 41.2 (N(CH ) ), 43.5 (C-7), 48.1 (C-4), 50.8
3 2
3
a
0
0
0
0
s, 6-CH ), 1.56–1.66 (3H, m, 7-H /14-H /4 -H ), 2.07–2.11
b
(2H, m, 4-H/7-H ), 2.18 (6H, s, N(CH ) ), 2.39–2.44 (1H,
b 3 2
m, 3 -H), 2.50–2.57 (2H, m, 8-H/2-H), 3.13 (1H, m, 2 -H),
3
5
3
(C-2), 66.2 (C-3 ), 68.8 (C-5 ), 70.1 (C-3), 72.1 (C-2 ),
78.3 (C-13), 83.4 (C-6), 84.9 (C-5), 89.1 (C-12), 104.9
3
a
b
0
0
0
(C-1 ), 120.3 (C-9), 125.2 (C-11), 145.5 (C-10), 178.5
0
.36–3.39 (1H, m, 5 -H), 3.42 (1H, d, J¼11.2 Hz,
(C-1); IR (film, CH Cl ) n¼2969 (s), 2934 (s), 2881 (w),
2
2
0
-H), 4.07 (1H, d, J¼7.2 Hz, 1 -H), 4.22 (1H, d, J¼5.0 Hz,
2856 (m), 1736 (s), 1461 (m), 1372 (w), 1250 (m), 1173
(s), 1125 (w), 1098 (s), 1049 (s), 1032 (m), 993 (w).
-H), 4.97 (1H, dd, J¼11.6, 2.4 Hz, 13-H), 5.99 (1H,
s, 11-H); d (75 MHz; CDCl ): ꢁ4.4/ꢁ4.3/ꢁ4.2/ꢁ3.0
C
3
(
(CH ) C(CH ) Si), 10.3 (14-CH ), 11.9 (4-CH ), 13.0 (8-
3 3 3 2 3 3
Acknowledgements
CH ), 16.2 (2-CH ), 18.5/18.6 ((CH ) C(CH ) Si), 21.2
3
3
3 3
3 2
0
5 -CH ), 22.9 (12-CH ), 24.1 (C-14), 25.7 (10-CH ), 26.0/
3 3 2
(
0
6.2 ((CH ) C(CH ) Si), 29.3 (C-4 ), 30.0 (6-CH ), 40.7
3 3 3 2 3
We thank Alpharma AS and The Norwegian Research Coun-
cil for financial support and a research fellowship (S.G.).
2
(
C-8), 41.2 (N(CH ) ), 43.6 (C-7), 48.3 (C-4), 50.6 (C-2),
3 2
0
3), 83.9 (C-6), 84.7 (C-5), 88.4 (C-12), 105.0 (C-1 ),
0
0
6
1
1
6.2 (C-3 ), 68.9 (C-5 ), 70.0 (C-3), 72.1 (C-2 ), 78.1 (C-
0
19.4 (C-9), 133.8 (C-11), 139.6 (C-10), 178.4 (C-1); IR
References and notes
(
film, CH Cl ) n¼2969 (s), 2934 (s), 2882 (w), 2856 (m),
2
2
1736 (s), 1473 (w), 1461 (m), 1381 (w), 1373 (w), 1250
w), 1172 (s), 1124 (m), 1098 (s), 1067 (m), 1048 (s),
1. Asaka, T.; Manaka, A.; Sugiyama, H. Curr. Top. Med. Chem.
2003, 3, 961–989.
2. Wu, Y.-J.; Su, W.-G. Curr. Med. Chem. 2001, 8, 1727–1758.
(
1
031 (m), 903 (w), 835 (s), 774 (m).
3
. Katz, L.; Ashley, G. W. Chem. Rev. 2005, 105, 499–527.
0
desmethylerythralosamine (20). A solution of 10-bromo-
methyl-2 O,3O-bis(tert-butyldimethylsilyl)-10-desmethyl-
4
.1.20. 10-Ethyl-2 O,3O-bis(tert-butyldimethylsilyl)-10-
4. Ruan, X.; Pereda, A.; Stassi, D. L.; Zeidner, D.; Summers,
R. G.; Jackson, M.; Shivakumar, A.; Kakavas, S.; Staver,
M. J.; Donadio, S.; Katz, L. J. Bacteriol. 1997, 179, 6416–
6425.
5. Katz, L.; Stassi, D. L.; Summers, R. G.; Ruan, X.; Pereda-
Lopez, A.; Kakavas, S. PCT 1998, WO 98/51695.
6. Gu, Y. G.; Zhang, X.; Clark, R. F.; Djuric, S. W.; Ma, Z. Tetra-
hedron Lett. 2004, 45, 3051–3053.
0
erythralosamine (19) (0.064 g, 0.080 mmol) in NMP (1 ml)
was degassed for 1 h before the Pd (dba) $CHCl complex
2
3
3
(
0.002 g, 0.002 mmol) and TFP (0.004 g, 0.016 mmol)
ꢀ
were added. The mixture was heated to 50 C to generate
the active catalyst and trimethylaluminium 2 M in hexane,
(
The resultant reaction mixture was heated at 100 C for
2
0.2 ml, 0.400 mmol) added carefully through a syringe.
ꢀ
4 h. The cold reaction mixture was filtered through a silica
7. (a) Flynn, E. H.; Sigal, M. V.; Wiley, P. F.; Gerzon, K. J. Am.
Chem. Soc. 1954, 76, 3121–3131; (b) Kurath, P.; Jones, P. H.;
Egan, R. S.; Perum, T. Experientia 1971, 27, 362.
8. Omura, S.; Tsuzuki, K.; Sunazuka, T.; Marui, S.; Toyoda, H.;
Inatomi, N.; Itoh, Z. J. Med. Chem. 1987, 30, 1941–1943.
9. Auricchio, S.; Fronza, G.; Meille, S. V.; Mele, A.; Favara, D.
J. Org. Chem. 1991, 56, 2250–2253.
10. Baker, W. R.; Clark, J. D.; Stephens, R. L.; Kim, K. H. J. Org.
Chem. 1988, 53, 2340–2345.
11. Stenmark, H. G.; Brazzale, A.; Ma, Z. K. J. Org. Chem. 2000,
65, 3875–3876.
12. Freiberg, L. A. Ger. Offen. 2,154,032, 15 pp, 1972 [Chem.
Abstr. 1972, 19965e].
13. SMART and SAINT. Area-Detector Control and Integration
Software Version 5.054; Bruker Analytical X-ray Instruments:
Madison, WI, 1998.
14. Sheldrick, G. M. SADABS Version 2.01. Program for Empirical
Correction of Area Detector Data; University of G o¨ ttingen:
Germany, 2000.
15. Sheldrick, G. M. SHELXTL, Structure Determination Pro-
grams Version 5.10; Bruker Analytical X-ray Instruments:
Madison, WI, 1997.
plug and the solvent was removed from the product by
distillation. The residual material was subjected to flash
chromatography on silica gel using hexane/Et O 4:1; yield
2
0
.053 g (84%) of a white crystalline material. HRMS:
M+1], 782.5383. Calcd for C H NO Si : 782.5417; d
H
[
(
2
0
4
2
80
8
2
500 MHz; CDCl ): 0.03/0.05/0.007/0.19 (4ꢂ3H, 4ꢂs,
3
ꢂ(CH ) C(CH ) Si), 0.84 (3H, t, J¼7.4 Hz, 14-CH ),
3
3
3 2
3
.88/0.90 (2ꢂ9H, 2ꢂs, 2ꢂ(CH ) C(CH ) Si), 0.92 (3H, d,
3
3
3 2
J¼7.2 Hz, 8-CH ), 0.95 (3H, d, J¼7.2 Hz, 4-CH ), 1.06
3
3
(
3H, d, J¼7.5 Hz, 2-CH ), 1.08 (3H, t, J¼7.2 Hz, 10-
3
0
CH CH ), 1.14 (3H, d, J¼6.1 Hz, 5 -CH ), 1.15–1.19 (1H,
2
3
3
0
m, 4 -H ), 1.24 (3H, s, 12-CH ), 1.32–1.35 (1H, m, 14-H ),
a
3
a
0
.47 (3H, s, 6-CH ), 1.56–1.65 (3H, m, 7-H /14-H /4 -H ),
3 a b b
1
1
1
2
3
.91–1.99 (1H, m, 10-CH ), 2.05–2.15 (3H, m, 4-H/7-H /
b
a
0
.44–2.54 (2H, m, 8-H/2-H), 3.13 (1H, m, 2 -H), 3.36–
0-CH ), 2.18 (6H, s, N(CH ) ), 2.40–2.43 (1H, m, 3 -H),
b 3 2
0
0
.39 (1H, m, 5 -H), 3.42 (1H, d, J¼11.3 Hz, 5-H), 4.05
0
(
4
1H, d, J¼7.1 Hz, 1 -H), 4.22 (1H, d, J¼4.9 Hz, 3-H),
.95 (1H, dd, J¼11.6, 2.4 Hz, 13-H), 5.45 (1H, s, 11-H);